Abstract

The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.

Figure 3

(A and B) The MEME motif discovery program was used to identify aa motifs enriched in controller TRAV24 sequences (A) and TRBV2 sequences (B) compared with corresponding sequences in treated patients. The MEME program was used in discriminative mode, which highlights differences between sequence datasets. The relative size of each aa symbol is proportional to its frequency in the HIC dataset, while the total height of aa symbols indicates the information content of the position in bits. (C and D) Frequency of public clonotypes (clono.) per 100 TRAV24 sequences (C) or per 100 TRBV2 sequences (D) for each of the 8 controllers (HIC) and 8 treated patients (HAART) studied. (E and F) Frequency of nucleotide sequences coding for a public clonotype per 100 TRAV24 sequences (E) and per 100 TRBV2 sequences (F). (C–F) Significant differences (P < 0.05) obtained by using the Mann-Whitney U test are reported.